Rationale for CD40 Pathway Blockade in Autoimmune Rheumatic Disorders Pucino, Valentina; Gardner, David; Fisher, Benjamin
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University of Birmingham Rationale for CD40 pathway blockade in autoimmune rheumatic disorders Pucino, Valentina; Gardner, David; Fisher, Benjamin DOI: 10.1016/S2665-9913(20)30038-2 License: Creative Commons: Attribution-NonCommercial-NoDerivs (CC BY-NC-ND) Document Version Peer reviewed version Citation for published version (Harvard): Pucino, V, Gardner, D & Fisher, B 2020, 'Rationale for CD40 pathway blockade in autoimmune rheumatic disorders', The Lancet Rheumatology, vol. 2, no. 5, pp. e292-e301. https://doi.org/10.1016/S2665- 9913(20)30038-2 Link to publication on Research at Birmingham portal General rights Unless a licence is specified above, all rights (including copyright and moral rights) in this document are retained by the authors and/or the copyright holders. The express permission of the copyright holder must be obtained for any use of this material other than for purposes permitted by law. •Users may freely distribute the URL that is used to identify this publication. •Users may download and/or print one copy of the publication from the University of Birmingham research portal for the purpose of private study or non-commercial research. •User may use extracts from the document in line with the concept of ‘fair dealing’ under the Copyright, Designs and Patents Act 1988 (?) •Users may not further distribute the material nor use it for the purposes of commercial gain. Where a licence is displayed above, please note the terms and conditions of the licence govern your use of this document. When citing, please reference the published version. Take down policy While the University of Birmingham exercises care and attention in making items available there are rare occasions when an item has been uploaded in error or has been deemed to be commercially or otherwise sensitive. If you believe that this is the case for this document, please contact [email protected] providing details and we will remove access to the work immediately and investigate. Download date: 30. Sep. 2021 Rationale for CD40 pathway blockade in autoimmune rheumatic disorders Valentina Pucino1,2 PhD; David H. Gardner1 PhD; Benjamin A. Fisher1,2 MD(Res) 1. Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham (UK) 2. National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre and Department of Rheumatology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK. * Correspondence to: Dr Benjamin Fisher Institute of Inflammation and Ageing College of Medical and Dental Sciences University of Birmingham Queen Elizabeth Hospital, Birmingham, B15 2WB Direct Line: +44 (0) 7956617385 Email: [email protected] 1 Abstract CD40 and CD40L (CD154) belong to the tumour necrosis factor receptor superfamily and are expressed by immune and non-immune cells. CD40L plays a central role in co-stimulation and regulation of the immune response via activation of CD40-expressing cells. Imbalance of the CD40/CD40L costimulatory pathway is reported in many autoimmune diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and Sjögren’s syndrome (SS) thus supporting its role in the breach of immune tolerance typical of these diseases. Targeting CD40/CD40L signalling may represent a novel therapeutic option for several autoimmune disorders. Key points: 1. CD40/CD40L signalling pathway regulates immune and non-immune cell responses 2. CD40/CD40L signalling is altered in autoimmune diseases such as SLE, RA, and SS 3. Early clinical trials programmes targeting CD40L were halted due to thrombotic adverse events 4. New therapeutic approaches targeting CD40 or using modified molecules against CD40L are currently being tested 5. Targeting CD40/CD40L signalling is a promising novel therapeutic strategy for reducing inflammation in autoimmune rheumatic disorders 2 1. Introduction CD40L/CD40 interactions exert profound effects on immune and non-immune cells (1-3). In a pathogenic setting, the deregulation of CD40 signalling has been observed in multiple autoimmune diseases (1-3). Conversely, therapeutic up-regulation of the CD40 pathway in cancer may have potent anti-tumor effects. Thus the CD40 pathway has long been an attractive therapeutic target for treating autoimmune diseases; however, early clinical trials of monoclonal antibodies blocking CD40 ligand (CD40L) were halted due to platelet-related thromboembolic complications (4). CD40 is a transmembrane type I glycoprotein which belongs to the tumour necrosis factor (TNF) gene superfamily and behaves as a co-stimulatory molecule. It is constitutively expressed by B cells and antigen presenting cells including monocytes, neutrophils and dendritic cells, and may be expressed on other cell types such as epithelial cells, endothelial cells, smooth muscle cells, fibroblasts, and platelets (2). Its ligand, CD40L (CD154), is a type II transmembrane protein which exists in soluble (sCD40L) or membrane-bound form. CD40L is mainly expressed on activated T cells, B cells, natural killer, platelets, endothelial, epithelial, and smooth muscle cells (1, 2). Soluble CD40L is mainly produced by platelets (5) and activated T cells (6) and is functional, being capable of enhancing platelet activation and B cell proliferation (7). The wide expression of this co- stimulatory machinery indicates the pivotal roles they play in different cellular immune processes. In this review, we will first outline the role of CD40–CD40L in the biology of immune cells. We will then review published data on the role of the CD40–CD40L signalling pathway in autoimmune rheumatic diseases and, finally, novel approaches to targeting the pathway for clinical efficacy. 2. Co-stimulation The requirement for B and T cell co-stimulation during the initiation of adaptive immune responses acts as a checkpoint that is involved in maintaining immune tolerance. A failure to regulate these 3 signals can underlie the development of autoimmunity which makes them an attractive therapeutic target. Similarly, in cancer therapy, the inhibition of regulatory pathways such as CTLA-4 and PD-1 has been utilised successfully with the aim of propagating anti-tumor immunity. The requirement for CD28 is of fundamental importance to the initiation of adaptive immune responses in that naïve T cells are dependent upon CD28-signalling for activation and proliferation. The CD28 pathway has been effectively targeted in the treatment of rheumatoid arthritis (RA) with abatacept [Orencia; CTLA-4Ig; (8)]. Although patient responses to therapy can be variable, a subpopulation of patients appear to respond particularly well to treatment. Nevertheless, a key problem associated with CD28-blockade is the inability to effectively time the treatment. Specifically, patients are unlikely to present in the clinic until many years after tolerance mechanisms were initially bypassed and autoimmune responses are initiated. At this stage, activated/memory T cells become less dependent upon CD28-costimulation and are located at sites of inflammation where features of the local microenvironment diminish the efficacy of therapy. Indeed, attention has turned towards treating patients at earlier stages of the disease (9), even so far as to treat individuals who are at risk of RA development prior to the onset of active synovitis (10). Although, CD28 can continue to play a role in an ongoing immune response, the upregulation of other costimulatory pathways implies some redundancy. These alternate co-stimulatory pathways include other members of the CD28 family and wider Immunoglobulin superfamily and TNF-receptor superfamily members which cooperate with/take over from CD28 in driving the maintenance, differentiation and effector function of activated T cell populations (11). This hierarchical arrangement in the relative contributions of various costimulatory and inhibitory pathways brings additional targets for biological therapies in autoimmunity with the capacity to modulate features of lymphocyte effector function which are the basis of immune mediated pathologies (Figure 1). For example, (ICOS (Inducible T cell co-stimulator) expression is driven by CD28 signaling in activated T cells (12). This mediates signalling that is important to the germinal centre reaction via the maintenance of T follicular helper cells (Tfh) (13, 14) which places the ICOS- 4 ICOS-L pathway at the center of B/T Cell crosstalk and therefore an appealing target in B cell mediated immune pathologies. Indeed, ICOS-L has been targeted via a fully human monoclonal antibody (AMG-557; prezalumab) although a phase 2a clinical trial to evaluate the safety and efficacy of AMG 557 in subjects with primary Sjögren’s syndrome showed no efficacy. It is possible that this is associated with redundancy created by the presence of additional costimulatory pathways. The CD40-CD40L pathway fulfils multiple roles within this co-stimulation hierarchy. By driving Antigen Presenting Cell (APC) activation, including the expression of the CD28 ligands CD80 and CD86 (15, 16), CD40 signaling could be seen to sit above CD28 in the hierarchy by licensing effective CD28 co-stimulation. However, the CD40-CD40-L also forms an integral part of T cell effector function through a key role that is played in B/T cell crosstalk. This multifaceted role that is played in the generation of an adaptive immune responses has generated significant interest in the pathway as a target for therapy in autoimmune/inflammatory diseases. 3. CD40L/CD40 signalling in immune cells The